The fundamental roles of innate and adaptive host responses are to recognize and eradicate invading antigens, pathogens or altered self components to restore tissue integrity and homeostasis. While resolution can occur when the host response is normal, an exogenous insult cannot be contained when a critical host factor is inactivated, dysregulated, or genetic and/or environmental factors conspire to result in chronic lung disease. In our proposal, this critical host factor is surfactant protein A (SP-A), a protein that lines the epithelial surfaces in the lung. Normal SP-A can attenuate allergic inflammation, but SP-A that is altered or abnormal as a consequence of genetic polymorphisms and/or oxidative changes has abrogated ability to defend the host from environmental insults leading to excessive bronchoconstriction and allergic inflammation. Our preliminary studies in vitro, in animal models of airway inflammation and in patients with asthma have identified specific defects in the role of SP-A in the innate immune response that contribute to the persistence or exacerbation of asthma and allergic disease. The central hypothesis to be tested is that SP-A, which normally regulates innate immunity and protects the host from persistence and exacerbation of asthma, is dysfunctional in asthma. These projects will employ specific environmental challenges (infection and ozone exposure) to test the ability of SP-A to modulate allergic inflammation in asthma, and whether allelic variants of SP-A, insufficient quantities or oxidation are responsible for dysfunction of SP-A in asthma. Project 1 will evaluate the ability of human SP-A from asthmatic subjects and allelic variant SP-A to modulate the innate and adaptive responses to infection and ozone exposure, respectively, in the human macrophage and airway epithelial cell. Project 2 will employ murine models of ovalbumin sensitization and challenge to determine if asthmatic SP-A and allelic variants of SP-A effectively modulate inflammaton induced by an infectious challenge. Project 3 will determine whether a specific SP-A polymorphisms modulate differential sensitivity to ozone exposure in asthma (physiologic and mechanical), and whether SP-A itself undergoes oxidation during in vivo ozone exposure in human asthma.